Dataset Information

Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity.

ABSTRACT:

Objective

Sympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects.

Methods

To address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2^LyzM-/- mice).

Results

These animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2^LyzM-/- mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation.

Conclusions

Our studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.

SUBMITTER: Rached MT

PROVIDER: S-EPMC6358539 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity.

Rached Marie-Therese MT Millership Steven J SJ Pedroni Silvia M A SMA Choudhury Agharul I AI Costa Ana S H ASH Hardy Darran G DG Glegola Justyna A JA Irvine Elaine E EE Selman Colin C Woodberry Megan C MC Yadav Vijay K VK Khadayate Sanjay S Vidal-Puig Antonio A Virtue Samuel S Frezza Christian C Withers Dominic J DJ

Molecular metabolism 20181128

<h4>Objective</h4>Sympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrop ...[more]

PMID: 30553769

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Project description:Aim: We generated mice lacking Irs2 which mediates signaling pathways from insulin and IL-4 specifically in lyzM Cre expressing cells. We isolated BMDM from control and Irs2LyzM-/- mice and compared their differential gene expression under veihicle, IL-4 and LPS treatment by performing mRNA sequencing studies. Methods: BMDM from control and Irs2LyzM-/- mice were treated for 24 hours with vehicle, IL-4 (10 ng/ml) or LPS (100 ng/ml). RNA integrity was confirmed and concentration measured using a Bioanalyzer. cDNA libraries were created from up to 5 μg total RNA. There were three (Irs2LyzM-/-) and four (control) biological replicates for each group and each biological replicate was divided into eight technical replicates and sequenced on individual lanes on the Illumina HiSeq 2000 (100 bp paired-end read length) at the Sanger Institute. Raw reads from the sequenced RNAseq libraries were mapped with Tophat splice junction aligner (Kim, Pertea et al. 2013), version 2.0.8 against Ensembl mouse genome reference sequence assembly (mm9) and transcript annotations. All parameters were set to default except inner distance between mate pairs (r = 130). Gene-based read counts were then obtained using the HTSeq count module (version 0.5.4p3). Differential expression analysis was performed on the counts data using the DESeq2 Bioconductor package (version 1.16.1). The GSEA preranked tool from GSEA version 2.2.4 was used forGeneset enrichment analysis. Gene ontology enrichment analysis was also performed using the topGo Bioconductor package separately for up and down-regulated genes in the comparisons analysed ( A. Alexa, J. Rahnenfuhrer, topGO: Enrichment Analysis for Gene Ontology. R package version 2.24.0 (2016)). Results: The mRNA seq. results reveal an anti- inflammatory transcriptional profile in LPS-treated Irs2LyzM-/- BMDM compared to control BMDM. Deletion of Irs2 in BMDM under all conditions (vehicle, IL-4 and LPS) manifest alteratons in genes involved in scavenging catecholamines and supporting increased sympathetic innervation.

Project description:Obesity is the principal symptom of metabolic syndrome, which refers to a group of risk factors that increase the likelihood of atherosclerosis. In recent decades there has been a sharp rise in the incidence of obesity throughout the developed world. Iso-α-acids, the bitter compounds derived from hops in beer, have been shown to prevent diet-induced obesity by increasing lipid oxidation in the liver and inhibition of lipid absorption from the intestine. Whereas the sharp bitterness induced by effective dose of iso-α-acids precludes their acceptance as a nutrient, matured hop bittering components (MHB) appear to be more agreeable. Therefore, we tested MHB for an effect on ameliorating diet-induced body fat accumulation in rodents. MHB ingestion had a beneficial effect but, compared to iso-α-acids and despite containing structurally similar compounds, acted via different mechanisms to reduce body fat accumulation. MHB supplementation significantly reduced body weight gain, epididymal white adipose tissue weight, and plasma non-esterified free fatty acid levels in diet-induced obese mice. We also found that uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) was significantly increased in MHB-fed mice at both the mRNA and protein levels. In addition, MHB administration in rats induced the β-adrenergic signaling cascade, which is related to cAMP accumulation in BAT, suggesting that MHB could modulate sympathetic nerve activity innervating BAT (BAT-SNA). Indeed, single oral administration of MHB elevated BAT-SNA in rats, and this elevation was dissipated by subdiaphragmatic vagotomy. Single oral administration of MHB maintained BAT temperature at a significantly higher level than in control rats. Taken together, these findings indicate that MHB ameliorates diet-induced body fat accumulation, at least partly, by enhancing thermogenesis in BAT via BAT-SNA activation. Our data suggests that MHB is a useful tool for developing functional foods or beverages to counteract the accumulation of body fat.

Dataset Information

Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity.

Objective

Methods

Results

Conclusions

Publications

Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity.

Similar Datasets

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